Publication Date

2015-07-21

Availability

Embargoed

Embargo Period

2017-07-20

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biomedical Engineering (Engineering)

Date of Defense

2015-06-15

First Committee Member

Herman S. Cheung

Second Committee Member

Jacqueline Sagen

Third Committee Member

Cherie Stabler

Fourth Committee Member

Edward A. Dauer

Abstract

DPN is the most frequently observed serious and chronic complication of diabetes. Although commonly believed that hyperglycemia is the major cause of DPN, a decrease in the level of neurotrophic factors, such as IGF-I, contributes to the pathogenesis of DPN. Systemic IGF-I injections in animal models of diabetes have proven successful to ameliorate and prevent further DPN degeneration. Our laboratory recently isolated a unique pluripotent stem cell from the neural crest (NCSC). The aim of this Doctoral work was to characterize our NCSC for expression, production, secretion of IGF-I, and transplant them into an animal model of diabetes with associated DPN. Additionally, NCSC were pre-committed to a neural lineage and also characterized for IGF-I, in the event that the undifferentiated NCSC would differentiate in-vivo. Male Sprague Dawley rats were induced with diabetes using STZ. Following four weeks of diabetes induction, the animals underwent weekly behavioral tests (Von Frey, Acetone, Paw Pressure) to establish baseline results prior to transplantation. After eight weeks of STZ induction, NCSC and NCSC-derived neural progenitor cells were transplanted into the thigh muscle of male Sprague Dawley rats. Behavioral tests were continued for four weeks following transplantation. Our results indicated that our NCSC secreted quantifiable levels of IGF-I, thus making them a suitable mini-pump of IGF-I for a cellular therapy approach to DPN. Our behavioral study results suggest that our NCSC and NCSC-derived neural progenitor cells provide some neuroprotection against further degeneration for both mechanical hyperalgesia and cold allodynia. These pilot results are encouraging to continue further work with NCSC as a cellular therapy for DPN.

Keywords

stem cells; diabetic peripheral neuropathy; neurogenesis; insulin-like growth factor I; neural crest

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